Development of Therapeutic-Grade Small Interfering RNAs by Chemical Engineering

Bramsen, Jesper B.; Kjems, Jørgen

doi:10.3389/fgene.2012.00154

Cited by 89 publications

(92 citation statements)

References 280 publications

(515 reference statements)

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“…Finally, therapies based on these principles rely on mechanisms distinct from existing drugs and thus may simultaneously improve the therapeutic ability of existing treatments and create new avenues for the treatment of drug-resistant or otherwise "untreatable" diseases [60,111,112]. sequence which assembles into a regular extended structure reminiscent of extended lattices in DNA nanotechnology [122].…”

Section: Rna Architectonic Approach (Tectorna)mentioning

confidence: 99%

“…Engineered RNA Nanodesigns for Applications in RNA Nanotechnology applications of RNA nanotechnology, is exemplified by currently over 20 different RNA-based therapeutics in clinical testing [60]. The majority of these are now in phase I or II clinical trials,…”

Section: Introductionmentioning

confidence: 99%

“…Compared to proteins and some synthetic materials, RNA nanomedicine offers the potential for high specificity and low toxicity treatments of many diseases through the utilization of naturally occurring mechanisms [58,60,62] The basis of RNA nanotechnology…”

mentioning

confidence: 99%

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Engineered RNA Nanodesigns for Applications in RNA Nanotechnology

Afonin¹,

Lindsay²,

Shapiro³

2013

DNA and RNA Nanotechnology

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IntroductionThe physical world presents a very different landscape at the nanometer scale. Physical phenomena such as inertia and gravity vanish from view; instead the interactions of matter and energy are dominated by other phenomena like wave-particle duality, uncertainty, and quantum electrodynamics. Nanotechnology is the engineering of functional systems at this scale, where the axioms that govern material and device design differ dramatically from those found at the macroscale level. More precisely, "nanotechnology" typically encompasses both the miniaturization of existing technologies to the nanoscale, and the discipline of engineering molecular-scale systems from the bottom up, producing constructs with fundamentally new qualities that revolutionize human engineering, from materials and manufacturing, electronics, and information technology, to medicine, biotechnology, energy, and even security. The array of goals and applications in nanotechnology intersects with an equally wide array of techniques and materials with their own emergent properties in the field. One such branch is concerned with the re-engineering of biological mechanisms, systems, and molecules in new forms with new utilities, broadly termed bio-nanotechnology.The field of nanotechnology taking advantage of nucleic acids has its origins in the work of Nadrian Seeman and coworkers who have, over the past 30 years, spearheaded the development of DNA nano-object fabrication utilizing DNA self-assembly [1][2][3][4][5][6]. Briefly, DNA nanotechnology uses the nature of DNA complementarity for the construction of DNA tiles with discrete secondary structure by canonical WatsonCrick interactions (G-C and A-T base pairing), using a relatively small number of structural rules fundamentally based on Holliday junction motifs. The use of these rules has resulted in the engineering and characterization of numerous DNA 3D nanoscaffolds with different connectiviities [7][8][9][10][11][12][13][14][15][16][17][18] and the ability for some of them to promote targeted delivery by functioning as DNA nano-capsules [19][20][21] or DNA nano-carriers for other functionialities [22]. Another powerful technique called DNA "origami", developed by Paul Rothemund [23], has been extended from its original scope for designing different 2D DNA shapes [24] and functional templates [25][26][27][28] Abstract Nucleic acids have emerged as an extremely promising platform for nanotechnological applications because of their unique biochemical properties and functions. RNA, in particular, is characterized by relatively high thermal stability, diverse structural flexibility, and its capacity to perform a variety of functions in nature. These properties make RNA a valuable platform for bio-nanotechnology, specifically RNA Nanotechnology, that can create de novo nanostructures with unique functionalities through the design, integration, and re-engineering of powerful mechanisms based on a variety of existing RNA structures and their fundamental biochemical properties. This review...

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Section: Rna Architectonic Approach (Tectorna)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Engineered RNA Nanodesigns for Applications in RNA Nanotechnology

Afonin¹,

Lindsay²,

Shapiro³

2013

DNA and RNA Nanotechnology

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“…These include low efficacy of mRNA inhibition, off targets, immunogenicity, low serum stability against the nucleases, cell specific delivery problems, target site recognition, accessibility and its cleavage. [7][8][9] To overcome most of these shortcomings, siRNA molecules are engineered by introducing chemical modifications. 9,10 Natural RNAs comprises of ribonucleotide-moieties, composed of sugar (Ribose), phosphate (phosphodiester bond) and nitrogenous bases Adenine (A), Guanine (G), Cytosine (C), and Uracil (U).…”

Section: Introcuctionmentioning

confidence: 99%

“…[7][8][9] To overcome most of these shortcomings, siRNA molecules are engineered by introducing chemical modifications. 9,10 Natural RNAs comprises of ribonucleotide-moieties, composed of sugar (Ribose), phosphate (phosphodiester bond) and nitrogenous bases Adenine (A), Guanine (G), Cytosine (C), and Uracil (U). 11 With modifications on these constituent molecules, sphere of their functionality has been enhanced.…”

Section: Introcuctionmentioning

confidence: 99%

SMEpred workbench: A web server for predicting efficacy of chemicallymodified siRNAs

et al. 2016

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Chemical modifications have been extensively exploited to circumvent shortcomings in therapeutic applications of small interfering RNAs (siRNAs). However, experimental designing and testing of these siRNAs or chemically modified siRNAs (cm-siRNAs) involves enormous resources. Therefore, in-silico intervention in designing cm-siRNAs would be of utmost importance. We developed SMEpred workbench to predict the efficacy of normal siRNAs as well as cm-siRNAs using 3031 heterogeneous cm-siRNA sequences from siRNAmod database. These include 30 frequently used chemical modifications on different positions of either siRNA strand. Support Vector Machine (SVM) was employed to develop predictive models utilizing various sequence features namely mono-, di-nucleotide composition, binary pattern and their hybrids. We achieved highest Pearson Correlation Coefficient (PCC) of 0.80 during 10-fold cross validation and similar PCC value in independent validation. We have provided the algorithm in the 'SMEpred' pipeline to predict the normal siRNAs from the gene or mRNA sequence. For multiple modifications, we have assembled 'MultiModGen' module to design multiple modifications and further process them to evaluate their predicted efficacies. SMEpred webserver will be useful to scientific community engaged in use of RNAi-based technology as well as for therapeutic development. Web server is available for public use at following URL address: http://bioinfo.imtech.res.in/manojk/smepred.

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